Journal of Crohns & Colitis最新文献

Introduction: Predictive biomarkers for treatment efficacy of ulcerative colitis [UC] treatments are lacking. Here, we performed a longitudinal study investigating the association and potential predictive power of genome-wide peripheral blood [PB] DNA methylation signatures and response to tofacitinib treatment in UC.

Methods: We recruited moderate-to-severe UC patients starting tofacitinib treatment, and measured PB DNA methylation profiles at baseline [T1], after 8 weeks [T2], and in a subset [n = 8] after a median of 20 weeks [T3] using the Illumina Infinium HumanMethylation EPIC BeadChip. After 8 weeks, we distinguished responders [R] from non-responders [NR] based on a centrally read endoscopic response [decrease in endoscopic Mayo score ≥1 or Ulcerative Colitis Endoscopic Index of Severity ≥2] combined with corticosteroid-free clinical and/or biochemical response. T1 PB samples were used for biomarker identification, and T2 and publicly available intraclass correlation [ICC] data were used for stability analyses. RNA-sequencing was performed to understand the downstream effects of the predictor CpG loci.

Results: In total, 16 R and 15 NR patients, with a median disease duration of 7 [4-12] years and overall comparable patient characteristics at baseline, were analysed. We identified a panel of 53 differentially methylated positions [DMPs] associated with response to tofacitinib [AUROC 0.74]. Most DMPs [77%] demonstrated both short- and long-term hyperstability [ICC ≥0.90], irrespective of inflammatory status. Gene expression analysis showed lower FGFR2 [pBH = 0.011] and LRPAP1 [pBH = 0.020], and higher OR2L13 [pBH = 0.016] expression at T1 in R compared with NR.

Conclusion: Our observations demonstrate the utility of genome-wide PB DNA methylation signatures to predict response to tofacitinib.

Background and aims: Anti-tumour necrosis factor [TNF] treatment failure in patients with inflammatory bowel disease [IBD] is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14.

Methods: DNA methylation from 1104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease [PANTS] study were assessed using the Illumina EPIC Beadchip [v1.0] at baseline and weeks 14, 30, and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 if they were assessed at subsequent time points and were not in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 94], with patients who responded at week 14 and when assessed at subsequent time points were in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 93].

Results: Overall, between baseline and week 14, we observed 4999 differentially methylated positions [DMPs] annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses. Epigenome-wide association [EWAS] analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at Week 14. Of these, 125 DMPs demonstrated shared associations with other common traits [proportion of shared CpGs compared with DMPs] including body mass index [23.2%], followed by C-reactive protein [CRP] [11.5%], smoking [7.4%], alcohol consumption per day [7.1%], and IBD type [6.8%]. EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients [Spearman's rho = -0.94, p <0.001].

Conclusion: Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy.

Background and aims: Inflammatory bowel disease [IBD] comprises an immune-mediated group of chronic gastrointestinal disorders. Patients with IBD may experience extraintestinal manifestations, such as hepatobiliary complications. This meta-analysis aims to assess the prevalence of different hepatic manifestations in IBD patients.

Methods: For this systematic review and meta-analysis, PubMed, Scopus, Web of Science, and Embase were searched until July 20, 2022, by specifying keywords for IBD, hepatic manifestations, and study type. Full texts of cohort studies in English that examined the prevalence of different hepatic manifestations were included in this study. The primary outcome was the overall prevalence of hepatic manifestations in IBD patients. For the statistical analysis, a proportion by random effect model meta-analysis was performed. The registration number for the protocol of this study in PROSPERO is CRD42022369595.

Results: From the 4421 articles retrieved from the primary search, 118 met the inclusion criteria and were included in the final analysis. After a pooled analysis of 1 729 128 patients, the overall prevalence of hepatic manifestations was 3.49% (95% confidence interval [CI]: 3.31-3.68%; I2: 99.55%). The pooled prevalence of non-alcoholic fatty liver disease in 228 216 patients was 26.1% [95% CI: 22.1-30.2%; I2: 99.018%]. After pooled analysis of 9642 patients, the prevalence of primary sclerosing cholangitis was 1.67% [95% CI: 1.47-1.88%; I2: 99.10%]. The pooled prevalence of biliary stones was 4.1% [95% CI: 3.6-4.7%; I2: 97.43%]. Autoimmune hepatitis (0.51% [95% CI: 0.26-0.75%]; I2: 85.36%) and portal vein thrombosis (0.21% [95% CI: 0.08-0.33%]; I2: 97.95%) are considered as rare manifestations.

Conclusion: This study summarizes the prevalence and importance of different hepatic manifestations in IBD patients. These findings are crucial for the management of extraintestinal manifestations, especially hepatic manifestations, in IBD patients.

Background and aims: Older patients with ulcerative colitis treated with tofacitinib are at risk for major cardiovascular events, thromboembolism, herpes zoster, and malignancies and, accordingly, its use is limited by the regulatory authorities. The aim of the present study was to evaluate the occurrence of adverse events and potential preventive measures.

Methods: We retrospectively evaluated patients treated with tofacitinib, divided into two groups according to comorbidities and age. Patient- and disease-related variables were recorded [primary non-response, loss of response, and persistence], together with deviations from the recommended induction regimen, ie, dose reduction, and concomitant treatments with anti-thrombotic therapy.

Results: The age-adjusted Charlson comorbidity index of Group 1 [n = 30] was ≥2 and that of Group 2 [n = 37] was ≤ 1. No differences were observed for primary or secondary treatment failures. Both groups achieved comparable steroid-free remission rates at 12 months [53% and 46%, respectively]. Herpes zoster occurred in two patients per group, and no more cases occurred after strict recombinant zoster vaccination. No major cardiovascular event or thromboembolism was registered. Half of patients in Group 1 were treated with a reduced induction dose of 5 mg twice daily and 47% were on concomitant anti-thrombotic therapy. Malignancies were registered in two patients from Group 1 and one patient from Group 2.

Conclusions: Modulation of induction dose and anti-thrombotic therapy may have contributed to prevent cardiological events and thromboembolism. The introduction of zoster vaccine virtually eliminated zoster risk after the first cases. Potential malignancies deserve a careful work-up of older patients before treatment start.

Background and aims: Home self-injection of the human anti-tumour necrosis alpha [anti-TNFα] monoclonal adalimumab complicates prospective serial-sampling studies. Although a recent study examined adalimumab levels and immunogenicity in Crohn's disease [CD] patients, prospective real-world data from ulcerative colitis [UC] patients are lacking.

Methods: A three-monthly home-visit programme from induction was established prospectively for UC patients. Clinical scores were determined at each visit, and sera were obtained for assessment of drug and anti-adalimumab antibody levels. Calprotectin was measured using a smartphone-based app. This cohort was compared to a parallel prospective cohort of adalimumab-treated CD patients [POETIC1].

Results: Fifty UC patients starting adalimumab [median follow-up 28 weeks] were compared to 98 adalimumab-treated CD patients [median follow-up 44 weeks]. Only 11/50 UC patients [22%] continued treatment to the end of the follow-up compared with 50/98 [51%] CD patients (odds ratio [OR] = 0.27, p = 0.001). Loss of response was significantly more common in UC patients [OR = 3.2, p = 0.001]. Seventeen patients [34%] in the UC cohort developed anti-adalimumab antibodies, 9/17 [52.9%] as early as week 2. There was no difference between patient cohorts in the overall development of anti-adalimumab antibodies [34% vs 30.6%, respectively, OR = 1.67, p = 0.67], nor was there a difference in early immunogenicity [OR = 1.39, p = 0.35]. There was no difference in low drug levels [<3 µg/mL] between the two cohorts [OR = 0.87, p = 0.83].

Conclusions: Loss of response to adalimumab therapy was significantly more common in the UC compared to the CD cohort and was driven by a higher rate of non-immunogenic, pharmacodynamic parameters.

Background and aims: We evaluated short- and long-term outcomes of temporary faecal diversion [FD] for management of refractory Crohn's disease [CD], focusing on outcomes in the biologic era.

Methods: Through a systematic literature review until March 15, 2023, we identified 33 studies [19 conducted in the biologic era] that evaluated 1578 patients with perianal and/or distal colonic CD who underwent temporary FD [with intent of restoring bowel continuity] and reported long-term outcomes [primary outcome: successful restoration of bowel continuity, defined as remaining ostomy-free after reconnection at a minimum of 6 months after diversion or at the end of follow-up]. We calculated pooled rates (with 95% confidence interval [CI]) using random effects meta-analysis, and examined factors associated with successful restoration of bowel continuity.

Results: Overall, 61% patients [95% CI, 52-68%; 50% in biologic era] experienced clinical improvement after FD. Stoma takedown was attempted in 34% patients [28-41%; 37% in biologic era], 6-18 months after diversion. Among patients where bowel restoration was attempted, 63% patients [54-71%] had successful restoration of bowel continuity, and 26% [20-34%] required re-diversion. Overall, 21% patients [17-27%; 24% in biologic era] who underwent FD were successfully restored; 34% patients [30-39%; 31% in biologic era] required proctectomy with permanent ostomy. On meta-regression, post-diversion biologic use and absence of proctitis was associated with successful bowel restoration after temporary FD in contemporary studies.

Conclusion: In the biologic era, temporary FD for refractory perianal and/or distal colonic CD improves symptoms in half the patients, and bowel continuity can be successfully restored in a quarter of patients.

Background and aims: Randomised controlled trials historically under-represent marginalised racial and ethnic populations. As incidence and prevalence of Crohn's disease in these groups rise, it is important to characterise their inclusion in randomised controlled trials on first-line and pipe-line medications.

Methods: PubMed was searched systematically for randomised controlled trials of biologic and small molecule inhibitor [SMI] medications, with a primary outcome related to efficacy following PRISMA guidelines. We used descriptive statistics to summarise demographic variables and meta-regression analyses to estimate temporal trends in racial inclusion.

Results: More than a half of trials did not report any racial/ethnic demographics [53.7%] and several reported racial demographics for only one race [20.9%]. When racial data were reported, Whites made up 90.2% of participants. Percentages of Black, Asian, Native American/Pacific Islander, and participants considered 'Other' averaged 2.9%, 11.6%, 0.5%, and 1.6% out of the total sample sizes of 3901, 3742, 828 and 4027, respectively. Proportional representation of White participants decreased over time [p <0.01] and proportional representation of Asian participants increased over time [p = 0.047]. In ordinal logistic regression, mean year of trial enrolment significantly increased the number of racial groups reported [p <0.001].

Conclusions: Half of published randomised controlled trials in Crohn's disease contain no racial or ethnic demographics, and the remaining often only have limited inclusion of Black, Native American/Pacific Islander, and Hispanic patients. Further work should characterise representation in observational and prospective trials. Researchers should work to: 1] increase reporting of racial and ethnic demographics; and 2] improve recruitment and retention of marginalised populations.

Background and aims: Creeping fat [CF] is a poorly understood feature of Crohn's disease [CD], characterized by the wrapping of mesenteric adipose tissue [MAT] around the inflamed intestine. The aim of this study was to investigate the transcriptional profile and compositional features of CF.

Methods: We collected 59 MAT samples: 23 paired samples from patients with CD (CF [CD-CF] and MAT around the uninflamed intestine [CD-MAT]) and 13 MAT samples from non-CD patients [Con-MAT]. Differentially expressed gene [DEG], functional pathway, cell deconvolution, and gene co-expression network analyses were performed.

Results: By comparing three different MAT samples, we identified a total of 529 DEGs [|log2FoldChange| > 1.5; false discovery rate < 0.05]. Of these, 323 genes showed an incremental pattern from Con-MAT to CD-MAT, and to CD-CF, while 105 genes displayed a decremental pattern. Genes with an incremental pattern were related to immune cell responses, including B- and T-cell activation, while genes with a decremental pattern were involved in cell trafficking and migration. Cell deconvolution analysis revealed significant changes in cellular composition between the CD-CF and Con-MAT groups, with increased proportions of B-cells/plasma cells [p = 1.16 × 10-4], T-cells [p = 3.66 × 10-3], and mononuclear phagocytes [p = 3.53 × 10-2] in the CD-CF group. In contrast, only the B-cell/plasma cell component showed a significant increase [p = 1.62 × 10-2] in the CD-MAT group compared to Con-MAT.

Conclusion: The distinct transcriptional profiles and altered cellular components of each MAT found in our study provide insight into the mechanisms behind CF and highlight its possible role in the pathogenesis of CD.

Backgrounds and aims: This interim analysis from the True North open-label extension [OLE] study examines efficacy and safety of approximately 3 years of continuous ozanimod treatment in patients with moderately to severely active ulcerative colitis.

Methods: Clinical responders after 52 weeks of ozanimod during the phase 3 True North study, who continued treatment in the OLE, were evaluated. Efficacy, including endoscopic and histological endpoints, was assessed during the OLE for approximately 2 additional years through OLE Week 94, using observed case [OC] and nonresponder imputation [NRI] analyses. Adverse events were monitored from True North baseline through OLE data cutoff and expressed as exposure-adjusted incidence rates.

Results: This analysis included 131 patients; 54% had achieved corticosteroid-free remission at True North Week 52. In OC analyses, clinical response, clinical remission, and corticosteroid-free remission were achieved by 91.4%, 69.1%, and 67.9% of patients, respectively, at OLE Week 94 [146 weeks of total treatment]. Similarly, endoscopic improvement, histological remission, and mucosal healing were achieved by 73.3%, 67.3%, and 56.3% of patients, respectively, at OLE Week 94. Efficacy rates were lower using NRI analyses, but maintenance of efficacy was demonstrated through OLE Week 94. No new safety signals emerged from this analysis. Serious infections, malignancy, cardiovascular events, and hepatic events occurred infrequently.

Conclusions: Among patients who achieved clinical response after 1 year of ozanimod treatment during True North, a high percentage sustained clinical and mucosal efficacy over 2 additional years in the OLE. No new safety signals were observed with long-term ozanimod use.